'If you are not preventing, curing and treating cancer, you are off target. You have not achieved the mandate.'

July 24, 2018

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By Sabin Russell / Fred Hutch News Service

Dr. Siddhartha Mukherjee addresses hundreds of Fred Hutch faculty members and staff during his seminar on July 23.

Photo By Robert Hood / Fred Hutch News Service

Columbia University physician and author Dr. Siddhartha Mukherjee packed the house at Fred Hutchinson Cancer Research Center in Seattle on Monday to talk about his research and his views on what he called “a mandate” to prevent, treat and cure the disease he famously labeled "The Emperor of All Maladies.”

That book, a comprehensive history of cancer, won the Pulitzer Prize for General Nonfiction in 2011 and inspired the Ken Burns documentary, "Cancer: The Emperor of All Maladies," which aired on PBS in 2015.

Mukherjee said that cancer researchers must understand the urgency that patients have to translate the dazzling discoveries in the lab into useful therapies.

“There is an impatience that’s growing in all communities, including in me, to bring therapeutics to human beings,” he said, and he called for more focus on the needs of patients.

“The mandate for the national cancer project was not to sequence genomes. It was to prevent, cure and treat cancer. That’s why we got the money we’ve got, that’s why we have the ambitions we have. … If you are not preventing, curing and treating cancer, you are off target. You have not achieved the mandate,’’ he said.

Mukerjee (center) chats with Fred Hutch faculty during a reception that followed his talk at the Seattle cancer research center.

Photo by Robert Hood / Fred Hutch News Service

'In Don Thomas' house'

Although Mukherjee’s work contained in its nearly 600 pages just one reference to Fred Hutch — a nod to the Nobel Prize winning bone marrow transplant work of Dr. E. Donnall Thomas — hundreds of faculty and staff members warmly welcomed the celebrity, who declared the Seattle cancer research center “one of my favorite places in the world to come to.”

As he surveyed the dazzling science he has witnessed as researcher and historian of cancer, Mukherjee told the Hutch gathering, “It is humbling to note that we are in Don Thomas’ house, because some of this began here and continues here.”

Mukherjee was introduced to the crowd by Fred Hutch President and Director Dr. Gary Gilliland, who was a professor at Harvard Medical School and got to know the rising young star while he trained as an oncology fellow at Dana-Farber Cancer Institute in Boston.

“He was one of the most creative and innovative fellows I ever met,” said Gilliland. He recalled that Mukherjee had developed laboratory tests to study the tumor microenvironment “back before it was fashionable.” Gilliland lauded Mukherjee's current wide-ranging studies that include a new class of stem cells involved in bone growth, the metabolic effects of a high-fat, low-carbohydrate diet on cancer drugs, and a strategy to engineer T cells to target acute myeloid leukemia.

Mukherjee's latest research

Mukherjee took his audience on a deep dive into his research, which he described as an effort to go beyond “the monomaniacal focus on the genome,” the complete roster of genes in every cell. Instead, he described his work as a “reconsideration of the human that’s wrapped around a cancer cell."

That work includes a paper published in July in Nature in collaboration with Dr. Lewis Cantley of Weill Cornell Medicine in New York City. The study in mice suggests that a popular “fat burner” ketogenic diet — low in sugars and high in fats — might overcome a weakness of an otherwise important class of experimental cancer drugs. These so-called PI3K inhibitors are intended to target one of the most common mutations found in cancers, including about one third of breast cancers.

The problem with these drugs, which disrupt the breakdown of certain sugars, is that they cause the body to respond with a spike in insulin, a hormone that can speed up the growth of the same tumors these drugs are meant to stop. The New York researchers reported that feeding mice a ketogenic diet reduced blood insulin and restored the anti-tumor efficiency of these compounds, a finding with significant implications for a raft of PI3K inhibitors undergoing clinical trials.

“Don’t try this at home,” Mukherjee cautioned. He noted that the ketogenic diet in these mouse experiments only worked in conjunction with administration of the drugs, and that studies have shown that by itself, the diet can accelerate progression of some cancers, such as acute myeloid leukemia.

He also described a second area of research that Gilliland described as “kind of a reverse twist” on CAR T-cell therapies, which typically reprogram immune cells to seek out proteins, or antigens, on the surface of cancer cells and then destroy them. This approach has not worked as well in acute myeloid leukemia, because researchers have found few surface antigens on AML cancer cells that do not also exist in healthy blood cells. Therefore, unfortunately, the engineered CAR T cells often kill healthy myeloid cells, which humans cannot live without.

Mukherjee’s strategy starts with removing a surface protein, known as CD33, from donated umbilical cord blood cells. CD33 is shared by normal and malignant cells, but normal myeloid cells apparently do not need it. Next, CAR T cells that recognize CD33 are infused into the patient, wiping out both cancer cells and healthy myeloid cells alike. But the super-powered T cells spare those transplanted engineered cord blood cells because they lack the telltale CD33 antigen. The hope is these transplanted cord blood cells would engraft in the patient’s bone marrow, giving rise to a healthy population of myeloid cells. (A human application is still far off in the future.)

An updated 'Emperor', a new 'Gene' documentary

The author also had some publishing news to share. He has signed a contract to write an updated version of "The Emperor of All Maladies" in 2020, five years sooner than originally planned. “You can buy it again!” he said to his audience.

He also confirmed the filmmaker Burns will be making a documentary based on one of Mukherjee’s subsequent books, “The Gene,” his 2016 history of genetics.

Fred Hutch scientists would clearly like to see more mention of the pioneering research done in the Pacific Northwest in New York-based Mukherjee’s next effort. He readily agreed with an audience query from Dr. Denise Galloway that his next Emperor should deal more with the approximately 20 percent of worldwide cancers caused by pathogens. Galloway, who holds a Fred Hutch 40th Anniversary Chair, is director of the Pathogen-Associated Malignancies Integrated Research Center, an interdisciplinary program at the Hutch focused on such cancers. “It is one place I thought was relatively neglected,” he said.

During Mukerjee's visit to Fred Hutch, he also sat down with Gilliland for a discussion about recent advances in cancer research and his future writing plans. A video of that interview, originally posted on Facebook, is available here.

Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at srussell@fredhutch.org.

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